Patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) have few treatment prospects and a poor prognosis. In the first-line setting, patients are primarily treated with Erbitux® (cetuximab, Merck KGaA/Bristol-Myers Squibb/Eli Lilly) plus chemotherapy and in later lines of therapy may be treated with Erbitux monotherapy or a variety of other single-agent systemic therapies. No new targeted therapies have been approved since 2011, which was Erbitux’s frontline approval in combination with 5-fluorouracil and platinum agents. The unmet need for this indication is illustrated by the fact that only one-half of patients will receive second-line treatment, while even fewer patients will receive third-line therapy or beyond.1

Patients with head and neck cancer will be cheered that the gains achieved by the new immunotherapies in indications such as melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) should soon be available for them and, moreover, that there will be options. The first late-stage data for this class of agents was presented today at the American Association of Cancer Research (AACR) as Dr. Maura Gillison presented results from the CheckMate-141 trial.2

CheckMate-141 randomized (2:1) 361 patients with R/M SCCHN to treatment with Opdivo® (nivolumab, Bristol-Myers Squibb) 3 mg/kg every two weeks or the investigator’s choice of chemotherapy (methotrexate, docetaxel or Erbitux). Although most patients (45%) received only one prior line of therapy, almost 20% of patients were treated with three or more prior lines of systemic therapy. CheckMate-141 was stopped at its interim endpoint in January after crossing the defined threshold for meeting its overall survival (OS) primary endpoint, a 30% reduction in the risk of death. As reported at today’s session, patients treated with Opdivo enjoyed a 2.4-month OS improvement compared with patients treated in the control arm (7.5 months versus 5.1 months, HR 0.70, p=0.0101). Notably, at one year patients treated with Opdivo had twice the probability of remaining alive than patients on the control arm (one-year OS rate: 36.0% versus 16.6%). Moreover, the OS benefit may increase as 17.4% of patients are continuing Opdivo therapy compared with only 2.7% of patients on the control arm.

Biomarker analysis was performed to determine the predictive value for PD-L1 positivity (defined as staining ≥ 1% and seen in 57.3% of the total sample) and p16 status (a marker for HPV positivity). Although PD-L1-positive patients saw a greater benefit for Opdivo than PD-L1-negative patients did (Table 1), PD-L1 negative patients did see a trend to benefit with Opdivo (11% reduction in risk of death); however, the Kaplan-Meyer curve separated dramatically at the tail end and provides some hope for this subgroup. HPV positivity, as measured through p16 positivity, was not predictive of benefit.

Table 1: Efficacy Data from CheckMate-141

Opdivo

Investigator’s Choice

N

mOS, mos

N

mOS, mos

HR

All patients

240

7.5

121

5.1

0.70

PD-L1 ≥ 1%

88

8.7

61

4.6

0.55

PD-L1 < 1%

73

5.7

38

5.8

0.89

p16-positive

63

9.1

29

4.4

0.56

p16-negative

50

7.5

36

5.8

0.73

Source: Gillison, Abstract CT-099, AACR 2016

As might be expected from this class of inhibitors, Opdivo was better tolerated than the controls. Only 13.1% of patients reported Grade 3-4 adverse events on Opdivo compared with 35.1% of patients on the control arm. Noteworthy primary toxicities of all grades for Opdivo included endocrine abnormalities (7.6% versus 0.9%) and pneumonitis (2.1% versus 0.9%).

Bristol-Myers Squibb publically stated at the time of the early trial closure that it is in discussions with regulatory officials regarding filing. When Opdivo is approved, it will most likely need to immediately compete with Merck’s Keytruda® (pembrolizumab). Merck announced in early April that the U.S. Food and Drug Administration (FDA) granted priority review of its application for accelerated approval of Keytruda with a target action date of August 9, 2016. This application was based on updated results of the Phase Ib KEYNOTE-012 trial, which reported an overall response rate of 24.8%, median progression-free survival (PFS) of 2.2 months, and median OS of 9.6 months in head and neck cancer patients.3,4 Physicians will undoubtedly try to tease out efficacy and tolerability differences between the two agents, but generally the agents seem to be equally effective.

Merck has ongoing Phase III trials for Keytruda in first-line (KEYNOTE-048, NCT02358031 and more on this below) and relapsed (KEYNOTE-040; NCT02252042) treatment as well as a Phase II trial (KEYNOTE-055; NCT02255097). Although the data for KEYNOTE-055 has not been publically reported, it may be included in Merck’s application for accelerated approval. The data for Opdivo suggests that it could be an effective option in frontline: The one-year OS rate (36.0%) reported in CheckMate-141 in pretreated patients compares favorably with data from the first-line EXTREME study,5 which reported a 40% one-year OS rate for Erbitux in combination with a platinum agent and 5-fluorouracil. However, Opdivo might have difficulties once the frontline KEYNOTE-048 trial reports. Unlike other Keytruda trials, KEYNOTE-048 does not require patients to be PD-L1-positive, so physicians could treat all of their patients with this agent once approved. If that wasn’t enough competition, MedImmune and AstraZeneca have two ongoing combination trials for their PD-L1 inhibitor durvalumab with their CTLA-4 inhibitor tremelimumab: the frontline KESTREL trial (NCT02551159) and the relapsed EAGLE trial (NCT02369874).

As with other indications that immunotherapies have entered, increased competition means increased options for patients. Opdivo should enjoy its well-earned spotlight with the release of CheckMate-141 data. It will be interesting to see which new options – new immunotherapies or combinations with existing immunotherapies – patients can look forward to tomorrow.